Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance

Friedrich, Katrin; Wieder, Thomas; Haefen, Clarissa von; Radetzki, Silke; Jänicke, Reiner U.; Schulze‐Osthoff, Klaus; Dörken, Bernd; Daniel, Peter T.

doi:10.1038/sj.onc.1204342

Cited by 110 publications

(91 citation statements)

References 45 publications

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“…5,39 Cytochrome c forms an active complex with APAF-1, which recruits procaspase-9 and thereby leads to the final execution of the cell death by activating the downstream caspase cascade. 3,[7][8][9][10][11][12] The BAX/APAF-1/Caspase pathway of apoptosis may also be functional in death receptor triggered apoptotic cell death. This process presumably involves a Bid-dependent pathway leading to a conformational change in BAX.…”

Section: Discussionmentioning

confidence: 99%

“…5 Cytochrome c forms an active complex with APAF-1 that recruits procaspase-9 and thereby leads to the final execution of the cell death by activating the downstream caspase cascade. 3,[7][8][9][10][11][12] We have shown previously that loss of BAX expression correlates with a poor prognosis in patients with hepatic metastases of colorectal cancer undergoing surgical resection of liver metastases. 13 Similar data were obtained in diffuse aggressive nonHodgkin-lymphoma, 14 ovarian, 15 pancreatic 16 and esophageal cancer 17 where reduced BAX expression was also observed to be a negative prognostic factor.…”

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confidence: 98%

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Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Schelwies

Sturm

Grabowski

et al. 2002

Intl Journal of Cancer

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Deregulation of cell death pathways contributes to tumor development and to the clinical course of cancer disease. In patients with liver metastases of colorectal cancer, we have previously shown that an intact p53/BAX apoptotic pathway is a positive prognostic factor. Therefore, the purpose of our study was to determine the prognostic value of BAX protein expression and the mutational status of its upstream regulator p53 in primary colorectal adenocarcinoma. To this end, we analyzed retrospectively tumor samples of 116 patients who underwent surgery for colorectal adenocarcinoma and had a follow-up for a minimum of 5 years or until death (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Tumors were screened for p53 mutations and investigated for BAX protein expression. Overall median survival was 17 months. As expected, patients with UICC III tumors survived longer than patients with UICC IV tumors: 69 months vs. 8 months (p < 0.0001). UICC III tumors with high BAX expression were associated with a significantly better prognosis (p ‫؍‬ 0.009) than BAX low expressing tumors. The combined p53/BAX pathway analysis for the UICC Stage III group revealed the worst outcome for patients with a disrupted p53/ BAX pathway (i.e., BAX low/p53 mutated; p ‫؍‬ 0.004). In contrast, no significant effect of the p53/BAX status on survival was found in UICC IV tumors. Our study in primary adenocarcinoma of the colorectum shows for the first time that a disrupted p53/BAX pathway is associated with a poor clinical outcome in UICC III tumors. These data also confirm our previous report on the relevance of an intact p53/BAX pathway in liver metastasis of colorectal cancer. Nevertheless, we were not able to confirm this finding in the heterogenous subgroup of UICC IV tumors of the colorectum. Our study therefore provides the basis for the analysis of defects in p53/BAX (and additional genes) in a prospective trial that is the logical basis for future risk-adapted therapies.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Schelwies

Sturm

Grabowski

et al. 2002

Intl Journal of Cancer

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“…Overexpression of caspase-1, which regulates apoptosis in normal mammary epithelial cells (Boudreau et al, 1995), is known to be lethal in MCF-7 cells (Keane et al, 1996). In these models, signaling through caspase-3 is unlikely because the gene is truncated in MCF-7 cells (Friedrich et al, 2001); signaling through caspase-7 may dominate.…”

Section: One Component Of a Gene Networkmentioning

confidence: 99%

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

et al. 2003

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“…Depending on their concentration, many cytostatic substances cause necrotic, membrane damaging as well as apoptotic cell death (Wieder et al, 1998;Friedrich et al, 2001). We therefore determined the unspecific, cytotoxic effect of calicheamicin WII (further designated as calicheamicin) in BJAB cells by the determination of LDH release into the culture medium.…”

Section: Dose-dependent Induction Of Apoptosis By Calicheamicin Wiimentioning

confidence: 99%

Induction of apoptosis by enediyne antibiotic calicheamicin ϑII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

et al. 2003

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Calicheamicin 0II is a member of the enediyne class of antitumor antibiotics that bind to DNA and induce apoptosis. These compounds differ, however, from conventional anticancer drugs as they bind in a sequencespecific manner noncovalently to DNA and cause sequence-selective oxidation of deoxyriboses and bending of the DNA helix. Calicheamicin is clinically employed as immunoconjugate to antibodies directed against, for example, CD33 in the case of gemtuzumab ozogamicin. Here, we show by the use of the unconjugated drug that calicheamicin-induced apoptosis is independent from death-receptor/FADD-mediated signals. Moreover, calicheamicin triggers apoptosis in a p53-independent manner as shown by the use of p53 knockout cells. Cell death proceeds via activation of mitochondrial permeability transition, cytochrome c release and activation of caspase-9 and -3. The overexpression of Bcl-x L or Bcl-2 strongly inhibited calicheamicin-induced apoptosis. Knockout of Bax abrogated cell death after calicheamicin treatment. Thus, the activation of mitochondria and execution of cell death occur through a fully Baxdependent mechanism. Interestingly, caspase inhibition by the pancaspase-inhibitor zVAD-fmk interfered with mitochondrial activation by calicheamicin. This places caspase activation upstream of the mitochondria and indicates that calicheamicin-triggered apoptosis is enhanced through death receptor-independent activation of the caspase cascade, that is, an amplification loop that is required for full activation of the mitochondrial pathway. Oncogene (2003) 22, 9107-9120.

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Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance

Cited by 110 publications

References 45 publications

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

Induction of apoptosis by enediyne antibiotic calicheamicin ϑII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

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